Manufacturing of Drug Product, Dual Aβ/tau Vaccine for Clinical Trials

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Project Summary Immunotherapy is still considered a promising therapeutic strategy for AD prevention. Data from various immunotherapeutic studies support our long-standing tenet that immunogenic AD vaccines could at least delay disease progression when they target both Aβ and Tau pathological molecules at an early stage of the disease or even in healthy people at AD risk. Recently FDA announced emergency accelerated approval of mAb Aducanumab for treatment of early AD. However, it is impractical to use very expensive mAbs as a preventive treatment for healthy subjects due to the need for frequent (monthly) administration of high concentrations (700-800mg per IV injection) of this immunotherapeutic. In contrast, almost all effective vaccines are effective when they are used as a preventive treatment. Accordingly, the major goal of the IMM-NIA cooperative U01 AG-60965 program is to manufacture single vaccines targeting tau or Aβ, and a dual vaccine, targeting both pathological molecules together. Based on this goal within the scope of the current program, we worked with Gates Biomanufacturing Facility (GBF) to manufacture two components of the dual vaccine, AV-1980R and AV-1959R recombinant proteins (drug substances), in a GMP format for first-human Phase I clinical trials. GBF developed two drug substances, AV-1980R and AV-1959R, that were tested in pre-clinical IND-enabling safety/toxicology studies. While GMP manufacturing of the first component of the dual vaccine, AV-1980R, is initiated and will be completed in August 2022, unexpectedly, technical difficulties arose with the production of the second component, AV-1959R. AV-1959R appeared to be a more aggregation-prone protein than AV-1980R, which led to a different formulation and a substantial decrease in AV-1959R production yield. While these difficulties are not significant for single vaccines, AV-1959R or AV-1980R (IND preparation is ongoing), manufacturing/formulation optimization is required for the dual vaccine prior to preparation and submission of IND. GBF team has identified a technical path forward to protein yield increase and formulation based on their experience and analytical tools such as dynamic light scattering, SDS-PAGE, and reverse-phase HPLC. Therefore, this project aims to develop a formulation for AV-1959R, which will increase the production yield of AV-1959R, support short and long-term stability, and manufacture a final cGMP grade dual vaccine (drug product). The requested funds will cover the cost of process development/formulation optimization of AV-1959R, manufacturing of cGMP AV-1959R drug substance, formulation of dual vaccine, filling/lyophilization, packaging, and release tests, stability of drug product dual vaccine.